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Nutritive and Non-Nutritive Sweeteners

NNNS: Adverse Effects (2011)

Citation:

Schiffman SS, Buckley CE III, Sampson HA, Massey EW, Baraniuk JN, Follett JV, Warwick ZS. Aspartame and susceptibility to headache. N Engl J Med. 1987 Nov 5; 317(19): 1,181-1,185.

PubMed ID: 3657889
 
Study Design:
Randomized Crossover Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To determine incidence of headache after aspartame challenge in subjects who reported having headaches repeatedly after consuming products containing aspartame.

Inclusion Criteria:

Inclusion

  • History of headache and related neurologic symptoms within 24 hours after consuming products containing aspartame (as identified by prior complaints to G.D. Searle & Company (the NutraSweet Company), manufacturers of products with aspartame or the FDA)
  • Free of major medical problems
  • At least 18 years of age
  • Provided written informed consent
  • Refrained from ingesting products containing aspartame for 18 hours before entry into study.
Exclusion Criteria:

Exclusion

  • History of major medical problems, including seizures
  • Less than 18 years old
  • No history of reported headache after ingesting aspartame-containing products.
Description of Study Protocol:

Recruitment

All subjects were chosen from a pool of those submitting prior complaints linking headache to aspartame to:

  • G.D. Searle & Company (the Nutrasweet Company)
  • Manufacturers of products containing aspartame
  • FDA.

Design

  • Day One: Medical history and physical examination
  • Day Two: Hematologic studies, UAL, blood chemistry tests
  • Day Three: First challenge day; 10mg per kg aspartame challenge or placebo given at 8:00 A.M., 10:00 A.M. and 12 P.M.
  • Day Four: Washout of day three
  • Day Five: Second challenge day and crossover from day three; 10mg per kg aspartame challenge or placebo given at 8:00 A.M., 10:00 A.M. ad 12 P.M.
  • Day Six: Allergy testing.

Blinding Used

  • Researchers and participants were blinded to sequence of aspartame or placebo challenge
  • Test articles given in capsule that undistinguished placebo from aspartame challenge dose.

Intervention

30mg per kg aspartame (given at 10mg per kg three times per day during one of two challenge days).

Statistical Analysis

  • McNemar's test 
  • Power analysis revealed 90% power of detecting significant difference at 40 subjects.
Data Collection Summary:

Timing of Measurements

  • Day three: First challenge day participant got aspartame or placebo at 8:00 A.M., 10:00 A.M. and 12 P.M.
  • Day five: Crossover second challenge day participant got aspartame or placebo at 8:00 A.M., 10:00 A.M. and 12:00 P.M.

 Dependent Variables

Headache measured as:

  • Adverse clinical symptom: Headache and related symptom evaluated independently by subject and study investigator when they occurred. Used a zero-to-100 scale for absent to intolerable headache
  • Investigator evaluated severity of headache as mild, moderate or severe.

Blood Chemistry Measured

Relevant blood chemistry indexes (performed at onset of each subject's awareness of headache or other important symptoms during course of experimental challenge).

Independent Variables

  •  Placebo: Microcrystalline cellulose capsule
  • Crossover
    • Independent variable was 98% pure aspartame given at 10mg per kg three times a day
    • In 70kg person, this 30mg per kg dose is equivalent to 4L aspartame in a carbonated soft drink.

 

Description of Actual Data Sample:
  • Initial N: N=40
    • 12 male (30%)
    • 28 female (70%)
  • Attrition (final N): N=40
  • Age: 18.8 to 68.9 range, mean 33.5±1.90
  • Ethnicity: White, 36 (90.0)%; Black, one (2.5%); Asian, two (2.0%); Hispanic, one (2.5%). 

Anthropometrics

  • Height (cm) 166.8±1.37
  • Weight (kg) 76.9±3.49
  • Blood Pressure (mm Hg): Systolic, 118.4±2.49; Diastolic, 74.8±1.92.

Location

Subjects were studied as inpatients at Duke University Medical Center Research Unit.

 

Summary of Results:

Summary

  • Incidence rate of headache after aspartame (35%) was not significantly different from that after placebo (45%), P<0.50
  • No serious reactions were observed following aspartame
  • No treatment-related effects were detected in vital signs, blood pressure or plasma concentrations of cortisol, insulin, glucagon, histamine, epinephrine or norepinephrine.

Dependent Variable One: Headache, Adverse Effect

Symptom

Aspartame

Placebo

Both

Neither

Headache

8

12

6

14

Dizziness

3

3

1

33

Fatigue

3

3

0

34

Nausea

4

5

0

31

Numbness

0

1

0

39

Tinnitus

1

1

0

38

Visual Impairment

2

1

2

35

Anxiety

3

2

0

35

Disorientation

1

1

0

38

Other Symptoms

8

12

6

14

Any Symptom Except Headache

11

13

8

8

Severity Aspartame Placebo P-Value
Investigator
1.4±0.13
1.2±0.1
0.42
Patient (analogue scale)
41.0±7.05
40.5±5.78
0.95
Onset of Headache (number of hours after 8:00 a.m.)
5.7±1.79
4.7±1.28
0.64
Duration of Headache (number of hours)
6.2±1.71
4.3±01.17
0.36

Abnormal Blood Test Values

Norepinephrine and epinephrine levels and comparison with pulse pressure on study days without headache and before and during headache.

 

Without Headache

With Headache  

Before
During
P-Value
Norepinephrine (pg per ml) MEAN
329.8
251.2
349.4
<0.0002
SEM
20.4
32.1
32.6
 
Epinephrine (pg per ml)
25.1
18.7
25.6
<0.02
  SEM
2.1
2.1
2.8
 
Pulse Pressure (mm Hg) Mean
40.2
38.3
43.5
<0.01
SEM
1.1
1.3
2.0
 

 

Author Conclusion:

Incidence of headache after short-term challenge with 30mg of aspartame per kg was equivalent to that of placebo.

Funding Source:
Government: GCRC, NIH
Industry:
NutraSweet Corporation,
Food Company:
Reviewer Comments:
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? No
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? ???
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes